Bacterial communities co-develop with respiratory immunity early in life, linking dysbiosis to systemic monocyte signature and wheezing.

Early microbial colonization influences respiratory disease risk, yet mechanisms remain unclear. In a prospective birth cohort of 256 infants, we profiled bacterial, fungal, and viral communities in the upper airway and assessed local immune gene expression longitudinally and systemic gene expression at 1 year. Bacterial populations, not fungal or viral, correlated most strongly with immune development during the first 3 months, coinciding with composition shifts and immune-related gene expression changes, including interferon and adaptive immunity pathways. In contrast, the mycobiome and resident viruses showed no significant coevolution with host immunity. By 1 year, infants who previously wheezed displayed an upper airway microbiota enriched in Haemophilus influenzae and Moraxella, accompanied by a distinct local and systemic immune gene signature featuring elevated classical monocyte-related genes. These findings reveal a specific link between early-life bacterial dysbiosis, monocyte-related immunity, and wheezing onset, suggesting potential targets for early intervention in respiratory disease.